Project summary (Core 1) This proposal brings together the translational medicine and research expertise of Dana-Farber Cancer Institute (DFCI), Dana Farber/Harvard Cancer Center, and Massachusetts Institute of Technology (MIT) with the clinical research strength of Intergroupe Francophone du Myeloma (IFM) in France and the genomics expertise of the Sanger Institute in the UK to develop a curative strategy for MM. In this international collaborative renewal application, we now propose to build on our highly successful genomic, preclinical, clinical, and administrative strengths to address the next generation of questions that will ultimately lead to therapeutic advances for cure. Most importantly, our current study has confirmed that achieving MRD negative status provides significantly superior survival outcome. In this proposal, we will now undertake an international collaborative trial to address the next most important issue of how MRD status will inform our therapeutic decision algorithm (Project 1). Importantly, the large number of uniformly treated patients will allow us to both identify genomic and epigenomic correlates of disease behavior (Project 2) and identify molecular circuits and validate novel combination targeted therapeutic approaches (Project 3) as well as to define the mechanisms and clinical implications of genomic instability in MM (Project 4). This unique international collaborative effort requires significant co-ordination of effort, integration of strategies, monitoring and oversight of various functions, and communication between investigators at various dispersed sites. The key function of Core A is integration of the research efforts and communication between investigators. Scientific and administrative integration is essential to assure successful interaction between the four Projects, as well as between the laboratory and clinical components within and between projects in this multinational multi-institutional program. Therefore, this central core will provide the link between various projects and successfully co-ordinate the clinical study and the proposed correlative science. To aid in achieving these goals, Core A will: monitor the timely conduct of the clinical study and assure progress in tissue collection, processing and usage to co- ordinate interaction between the clinical and correlative science studies (Specific Aim 1); co-ordinate communication, and exchange of data between investigators at various international sites (Specific Aim 2); provide necessary resources, fiscal oversight and administrative support for projects and cores (Specific Aim 3); facilitate intra-programatic interactions, meetings, travel and Internal and External Advisory Committees (Specific Aim 4).